Yang Youjun, Cheng Zongyue, Tang Hua, Jiao Huifeng, Sun Xuan, Cui Qiuzhu, Luo Fei, Pan Haili, Ma Chaolin, Li Baoming
Center for Neuropsychiatric Disorders, Institute of Life Science, Nanchang University, Nanchang 330031, P.R. China.
Cereb Cortex. 2017 May 1;27(5):2871-2884. doi: 10.1093/cercor/bhw121.
Adverse early-life experience such as depriving the relationship between parents and children induces permanent phenotypic changes, and impairs the cognitive functions associated with the prefrontal cortex (PFC). However, the underlying mechanism remains unclear. In this work, we used rat neonatal maternal separation (NMS) model to illuminate whether and how NMS in early life affects cognitive functions, and what the underlying cellular and molecular mechanism is. We showed that rat pups separated from their dam 3 h daily during the first 3 postnatal weeks alters medial prefrontal cortex (mPFC) myelination and impairs mPFC-dependent behaviors. Myelination appears necessary for mPFC-dependent behaviors, as blockade of oligodendrocytes (OLs) differentiation or lysolecithin-induced demyelination, impairs mPFC functions. We further demonstrate that histone deacetylases 1/2 (HDAC1/2) are drastically reduced in NMS rats. Inhibition of HDAC1/2 promotes Wnt activation, which negatively regulates OLs development. Conversely, selective inhibition of Wnt signaling by XAV939 partly rescue myelination arrestment and behavior deficiency caused by NMS. These findings indicate that NMS impairs mPFC cognitive functions, at least in part, through modulation of oligodendrogenesis and myelination. Understanding the mechanism of NMS on mPFC-dependent behaviors is critical for developing pharmacological and psychological interventions for child neglect and abuse.
早期不良经历，如剥夺亲子关系，会导致永久性的表型变化，并损害与前额叶皮质（PFC）相关的认知功能。然而，其潜在机制仍不清楚。在这项研究中，我们使用大鼠新生期母婴分离（NMS）模型来阐明早期生活中的NMS是否以及如何影响认知功能，以及潜在的细胞和分子机制是什么。我们发现，在出生后的前三周，每天将幼鼠与其母鼠分离3小时，会改变内侧前额叶皮质（mPFC）的髓鞘形成，并损害依赖mPFC的行为。髓鞘形成似乎是依赖mPFC行为所必需的，因为少突胶质细胞（OLs）分化的阻断或溶血卵磷脂诱导的脱髓鞘会损害mPFC功能。我们进一步证明，组蛋白去乙酰化酶1/2（HDAC1/2）在NMS大鼠中显著减少。抑制HDAC1/2会促进Wnt激活，而Wnt激活会对OLs发育产生负调节作用。相反，XAV939对Wnt信号的选择性抑制部分挽救了NMS导致的髓鞘形成停滞和行为缺陷。这些发现表明，NMS至少部分地通过调节少突胶质细胞生成和髓鞘形成来损害mPFC认知功能。了解NMS对依赖mPFC行为的作用机制对于开发针对儿童忽视和虐待的药物和心理干预措施至关重要。
